One of the principal mechanisms by which cellular regulation is effected is through the transduction of extracellular signals across the membrane that in turn modulate biochemical pathways within the cell. The process of phosphorylation, defined as the attachment of a phosphate moiety to a biological molecule through the action of enzymes called kinases, represents one course by which intracellular signals are propagated from molecule to molecule resulting finally in a cellular response. These signal transduction cascades are highly regulated and often overlapping as evidenced by the existence of an equal number of enzymes called phosphatases, which remove the phosphate moieties. Both proteins and lipids undergo phosphorylation within the cell, and kinases and phosphatases specific for each have been isolated.
Because phosphorylation is such a ubiquitous process within cells and because cellular phenotypes are largely influenced by the activity of these pathways, it is currently believed that a number of disease states and/or disorders are a result of either aberrant activation of, or functional mutations in kinases and phosphatases. Consequently, considerable attention has been devoted to the characterization of these proteins.
Ship-2 (also known as SH2-containing phosphatidylinositol phosphatase-2) is a phosphatase that selectively removes the phosphate from the 5-position of the inositol ring in inositol-containing lipids (Pesesse et al., Biochem. Biophys. Res. Commun., 1997, 239, 697-700). In doing so, Ship-2 plays a significant role in the termination of signal transduction cascades by regulating the level of soluble phospholipid messengers. This enzyme, expressed in a variety of hematopoietic cells, specifically dephosphorylates inositol (1,3,4,5)tetrakisphosphate and phosphatidylinositol (3,4,5)triphosphate (Pesesse et al., FEBS Lett., 1998, 437, 301-303). Ship-2 displays increased expression in heart, skeletal muscle and placenta. It has also been found to be expressed in dog thyroid cells where the expression was enhanced by TSH and EGF-stimulated cells (Pesesse et al., Biochem. Biophys. Res. Commun., 1997, 239, 697-700). Tyrosine phosphorylation of Ship-2 in SH-SY5Y cells has been shown to occur in response to EGF, PDGR, NGF, IGF-1 or insulin (Habib et al., J. Biol. Chem., 1998, 273, 18605-18609). The kinetics of this phosphorylation correlated with the activation of the Akt/PKB kinase pathway and the association of Ship-2 with the adapter protein Shc. This data suggest that 51C/SHIP2 may play a significant role in regulation of phosphatidylinositol 3'-kinase signaling by growth factors and insulin.
Currently, there are no known therapeutic agents which effectively inhibit the synthesis of Ship-2. Consequently there remains a long felt need for additional agents capable of effectively inhibiting Ship-2 function.
Antisense technology is emerging as an effective means for reducing the expression of specific gene products and may therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications for the modulation of Ship-2 expression.